Patch-like infusion device

ABSTRACT

A system and method for a patch-like, self-contained substance infusion device which provides one or more substantially hidden patient needles which can be placed in fluid communication with a fluid reservoir subassembly that includes a rigid bladder portion used in conjunction with a non-distensible bladder film, such as a metallized film. Simple removal of an interlock allows a disk, or Belleville spring assembly to apply an essentially even and constant pressure to the contents of the fluid reservoir assembly, and allows the device to then be attached to a skin surface via an adhesive contact surface. A push button activation assembly is provided which can then be used to release and seat one or more spring-loaded patient needles into the skin surface, and establish a fluid communication path between the patient needles and the pressurized fluid reservoir contents thereby delivering an infusion into the skin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit under 35 U.S.C. §119(e) from U.S.provisional patent application Ser. No. 60/397,038, entitled “Patch-LikeInfusion Device”, filed on Jul. 22, 2002; from U.S. provisional patentapplication Ser. No. 60/407,284, entitled “Patch-Like Infusion Device”,filed on Sep. 3, 2002; from U.S. provisional patent application Ser. No.60/420,233, entitled “Patch-Like Infusion Device”, filed on Oct. 23,2002; from U.S. provisional patent application Ser. No. 60/447,359,entitled “Patch-Like Infusion Device”, filed on Feb. 14, 2003; from U.S.provisional patent application Ser. No. 60/450,680, entitled “Patch-LikeInfusion Device”, filed on Mar. 3, 2003; and from U.S. provisionalpatent application Ser. No. 60/450,681, entitled “Patch-Like InfusionDevice”, filed on Mar. 3, 2003; the entire content of each of saidprovisional applications being expressly incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates generally to substance delivery devices,and is particularly concerned with a patch-like, wearable,self-contained substance infusion device that can be used to deliver avariety of substances or medications to a patient.

BACKGROUND OF THE INVENTION

A very large number of people require periodic delivery of drugs orother compounds to maintain their health. For example, people sufferingfrom diabetes use daily insulin infusions to maintain close control oftheir glucose levels. Currently, in the insulin infusion treatmentexample, there are two principal modes of daily insulin therapy. Thefirst mode includes syringes and insulin pens. These devices are simpleto use and are relatively low in cost, but they require a needle stickat each injection, typically three to four times per day. The second isinfusion pump therapy, which entails the purchase of an expensive pumpthat lasts for about three years. The initial cost of the pump is a highbarrier to this type of therapy. From a user perspective, however, theoverwhelming majority of patients who have used pumps prefer to remainwith pumps for the rest of their lives. This is because infusion pumps,although more complex than syringes and pens, offer the advantages ofcontinuous infusion of insulin, precision dosing and programmabledelivery schedules. This results in closer glucose control and animproved feeling of wellness.

As their interest in intensive therapy increases, users typically lookto insulin pumps. However, in addition to their high cost (roughly 8 to10 times the daily cost of syringe therapy) and limited lifetime,insulin pumps represent relatively old technology and are cumbersome touse. Also, from a lifestyle standpoint, the tubing (known as the“infusion set”) that links the pump with the delivery site on the user'sabdomen is very inconvenient and the pumps are relatively heavy, makingcarrying the pump a bother.

However, patients on oral agents eventually move to insulin, andexisting pump therapy is very expensive. Interest in better therapy ison the rise, accounting for the observed growth in pump therapy andincreased number of daily injections. In this and similar infusionexamples, what is needed to fully meet this increased interest is a formof insulin delivery or infusion that combines the best features of dailyinjection therapy (low cost and ease of use) with those of the insulinpump (continuous infusion and precision dosing) and that avoids thedisadvantages of each.

Several attempts have been made to provide ambulatory or “wearable” druginfusion devices that are low in cost and convenient to use. Some ofthese devices are intended to be partially or entirely disposable. Intheory, devices of this type can provide many of the advantages of aninfusion pump without the attendant cost and inconvenience.Unfortunately, however, many of these devices suffer from disadvantagesincluding user discomfort (due to the gauge and/or length of injectionneedle used), compatibility and interaction between the substance beingdelivered and the materials used in the construction of the infusiondevice, and possible malfunctioning if not properly activated by theuser (e.g., “wet” injections resulting from premature activation of thedevice. Difficulties in manufacturing and in controlling needlepenetration depth have also been encountered, particularly when shortand/or fine-gauge injection needles are used, and the possibility ofcausing needle-stick injuries to those who come into contact with theused device has also been problematic.

Accordingly, a need exists for an alternative to current infusiondevices, such as infusion pumps for insulin, that further providessimplicity in manufacture and use for periodic delivery of drugs andother compounds to the patient.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a patch-like infusiondevice which can be conveniently worn against the skin while providinginfusion of a desired substance.

Another object of the present invention is to provide a patch-likeinfusion device which provides a hidden patient needle or needles priorto and during use, unlike a conventional syringe.

Another object of the present invention is to provide a patch-likeinfusion device which provides minimal discomfort by using one or moremicroneedles.

Another object of the present invention is to provide a patch-likeinfusion device which can be secured to a patient via an adhesivesurface.

Another object of the present invention is to provide a patch-likeinfusion device which provides a pressurizing content reservoir.

Another object of the present invention is to provide a patch-likeinfusion device which provides a pressurizing content reservoir using abladder and Belleville spring assembly.

Another object of the present invention is to provide a patch-likeinfusion device which allows pressurizing the contents of a contentreservoir through a single or an optional secondary energizing step.

Another object of the present invention is to provide a patch-likeinfusion device which allows pressurizing the contents of a contentreservoir by removing a Belleville spring retaining pin via a pullhandle assembly in a single or an optional secondary energizing step.

Another object of the present invention is to provide a patch-likeinfusion device which provides patient needle implantation and reservoircontent delivery through a single or an optional secondary activationstep.

Another object of the present invention is to provide a patch-likeinfusion device which can be activated via a reasonable force applied toa vertical or horizontal push button in a single or an optionalsecondary activation step.

Another object of the present invention is to provide a patch-likeinfusion device which allows pressurizing the contents of a contentreservoir, patient needle implantation and reservoir content deliverythrough a combined single energizing and activation step.

Another object of the present invention is to provide a patch-likeinfusion device which allows for visual inspection of the devicecontents before, during and after use.

Another object of the present invention is to provide a patch-likeinfusion device which automatically shields or covers the patient needleor needles upon intentional or accidental removal from the skin surface.

Another object of the present invention is to provide a patch-likeinfusion device which provides an interlock between the pull handleassembly and the push button to prevent accidental activation.

Another object of the present invention is to provide a patch-likeinfusion device which allows for removal of a patient needle cap, and/orpull handle assembly, and/or an adhesive cover in one or more motions.

Another object of the present invention is to provide a patch-likeinfusion device which facilitates self-injection and reduces oreliminates variations in injection techniques between users.

These and other objects are substantially achieved by providing a systemand method for a patch-like, wearable, self-contained substance infusiondevice which provides one or more substantially hidden patient needleswhich can be placed in fluid communication with a content reservoirassembly that includes a rigid bladder portion used in conjunction witha bladder film, such as a metallized film which is typicallynon-distensible in normal use. Simple removal of a retaining pin allowsa disk or Belleville spring assembly to apply an essentially even andconstant pressure to the contents of the reservoir assembly, and allowsthe device to then be attached to a skin surface via an adhesive contactsurface. A push button activation assembly is provided which can then beused to release and seat one or more spring-loaded patient needles intothe skin surface, and establish a fluid communication path between thepatient needles and the pressurized reservoir contents therebydelivering an infusion of contents into the skin of the user.

BRIEF DESCRIPTION OF THE DRAWINGS

The various objects, advantages and novel features of the preferredembodiments of the present invention will be more readily appreciatedfrom the following detailed description when read in conjunction withthe appended drawings, in which:

FIG. 1 is a top perspective view of a first embodiment of a patch-likeinjector or infuser system using a side push button prior to energizingand activating;

FIG. 2 is a bottom perspective view of the first embodiment of apatch-like injector or infuser system using a side push button;

FIG. 3 is a top view of the first embodiment of a patch-like injector orinfuser system using a side push button;

FIG. 4 is a side elevational view of the first embodiment of apatch-like injector or infuser system using a side push button;

FIG. 5 is a bottom view of the first embodiment of a patch-like injectoror infuser system using a side push button;

FIG. 6 is a cross-sectional view (6-6 in FIG. 1) of the first embodimentof a patch-like injector or infuser system using a side push button;

FIG. 7 is a cross-sectional view (6-6 in FIG. 1) from a firstperspective angle of the first embodiment of a patch-like injector orinfuser system using a side push button;

FIG. 8 is a cross-sectional view (6-6 in FIG. 1) from a secondperspective angle of the first embodiment of a patch-like injector orinfuser system using a side push button;

FIG. 9 is a cross-sectional view (6-6 in FIG. 1) from a thirdperspective angle of the first embodiment of a patch-like injector orinfuser system using a side push button;

FIG. 10A is an exploded view of a reservoir subassembly of the firstembodiment shown in FIG. 1;

FIG. 10B is an exploded view of a housing subassembly of the firstembodiment shown in FIG. 1;

FIG. 10C is an exploded view of a push button subassembly of the firstembodiment shown in FIG. 1;

FIG. 11A is a cross-sectional view (6-6 in FIG. 1) of the firstembodiment shown in FIG. 1 prior to energizing and activation;

FIG. 11B is a cross-sectional view (6-6 in FIG. 1) of the firstembodiment shown in FIG. 1 after energizing and prior to activation;

FIG. 11C is a cross-sectional view (6-6 in FIG. 1) of the firstembodiment shown in FIG. 1 after activation;

FIG. 12 is a partial cross sectional view of the fluid path andreservoir subassembly of FIG. 10A;

FIG. 13 is a plot illustrating an example of insulin stability data fora reservoir subassembly in accordance with an embodiment of the presentinvention;

FIG. 14 is a plot illustrating an example of Belleville springcalculation data in accordance with an embodiment of the presentinvention;

FIG. 15A is a perspective view of a preferred embodiment of the patientneedle manifold patient contact surface configuration for the patientneedle manifold;

FIG. 15B is a perspective view of another patient contact surfaceconfiguration for the patient needle manifold of FIG. 15A;

FIG. 16A is a top perspective view of another embodiment of thesubassemblies of FIGS. 10A through 10C partially assembled;

FIG. 16B is a cross-sectional view of the subassemblies shown in FIG.16A prior to energizing and activation;

FIG. 16C is a cross-sectional view of the subassemblies shown in FIG.16A after energizing and activation;

FIG. 17A is a perspective view of a rotating safety shield feature of anembodiment of the present invention prior to energizing and activation;

FIG. 17B is a perspective view of a rotating safety shield feature of anembodiment of the present invention after energizing, activation andremoval from the user's skin surface;

FIG. 18A is a perspective view of an extending safety shield feature ofan embodiment of the present invention prior to energizing andactivation;

FIG. 18B is a perspective view of an extending safety shield feature ofan embodiment of the present invention after energizing, activation andremoval from the user's skin surface;

FIG. 19A is an exploded perspective view of a second embodiment of apatch-like injector or infuser system using a side push button;

FIG. 19B is a cross-sectional view of the patient needle/septum needlemanifold system of the second embodiment shown in FIG. 19A;

FIG. 19C is a cross-sectional view of the second embodiment shown inFIG. 19A prior to energizing and activation;

FIG. 19D is a cross-sectional view of the second embodiment shown inFIG. 19A after energizing and activation;

FIG. 20A is an exploded perspective view of a third embodiment of apatch-like injector or infuser system using a side push button;

FIG. 20B is a cross-sectional view of the third embodiment shown in FIG.20A prior to energizing and activation;

FIG. 20C is a cross-sectional view of the third embodiment shown, inFIG. 20A after energizing and activation;

FIG. 21A is an exploded perspective view of a fourth embodiment of apatch-like injector or infuser system using a top push button;

FIG. 21B is a partial cross-sectional view of the fourth embodimentshown in FIG. 21A prior to energizing and activation;

FIG. 21C is partial cross-sectional view of the fourth embodiment shownin FIG. 21A after energizing and activation;

FIG. 22 is an example of in vitro infusion data showing a flow rate overa period of 38 hours;

FIG. 23 is a plot illustrating an example of blood glucose level data;

FIG. 24 is a plot illustrating an example of blood insulin level data;

FIG. 25 is a plot illustrating an example of insulin response data;

FIG. 26 is a plot illustrating an example of pressure versusvolume-delivered data.

Throughout the drawings, like reference numerals will be understood torefer to like parts, components or structures.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Introduction

The embodiments of the present device described below can be used as aconvenient, patch-like device to deliver a pre-measured dose of asubstance, such as a drug or medication, to a user through an adhesiveattached infusion device. The device is self-contained and is attachedto the skin surface of the user by adhesive disposed on a bottomsurface. Once properly positioned and activated by the user, thepressure of a released Belleville spring on a reservoir surface withinthe device can be used to empty the contents of the flexible reservoirthrough one or more patient microneedles via a needle manifold. Thesubstance within the reservoir is then delivered through the skin of theuser by the microneedles which are driven into the skin by one or moresprings contained in the device. It will be understood that otherembodiments are possible in which the Belleville spring is replaced witha different type of stored energy device which may be mechanical,electrical and/or chemical in nature.

As will be appreciated by one skilled in the art, there are numerousways of carrying out the patch-like injection or infuser systemdisclosed herein. Although reference will be made to the embodimentsdepicted in the drawings and the following descriptions, the embodimentsdisclosed herein are not meant to be exhaustive of the variousalternative designs and embodiments that are encompassed by thedisclosed invention. In each disclosed embodiment, the device isreferred to as an infusor; however, the device may also injectsubstances at a much faster bolus rate than is commonly accomplished byinfuser devices. For example, the contents can be delivered in a periodas short as several seconds, or as long as several days.

General Structure

In a first embodiment of the present invention shown in FIGS. 1 through11, an infusion device 1000 includes a reservoir subassembly 100,including an upper housing 110, a reservoir base surface 120, at leastone Belleville spring 130, a retaining pin 140, fill plug 150, septum160 and reservoir film 170. The infusion device 1000 further includes ahousing subassembly 200, including a lower housing 210, and patientneedle manifold 220 having at least one patient needle 222 and amanifold film 224. The housing subassembly 200 further includes a needleshield 230, needle shield drive spring 232 and an adjustable needle cap240. An adhesive layer 250 is disposed upon the lower surface of thelower housing 210, and can be covered by a removable film (not shown),and a pull handle 260. A clip 270, such as an “E” clip can be used tosecure the retaining pin 140 to the pull handle 260. The infusion device1000 further includes a push button subassembly 300, including at leastone patient needle manifold drive spring 310, a push button slide 320,at least one septum needle 330, a septum needle sheath 340 and a fluidcommunication tube 350. A button face 360 can be provided to completethe push button subassembly 300. In the description below, the termreservoir is often used to describe the assembled and separate reservoirbase surface 120, fill plug 150, septum 160 and reservoir film 170 ofthe reservoir subassembly 100.

As noted above, the components of the embodiment shown in FIGS. 10Athrough 10C can be categorized into several subassemblies for ease indescription as presented below. Such subassemblies include, but are notlimited to, the reservoir subassembly 100, housing subassembly 200 andpush button subassembly 300. An assembled embodiment of the presentinvention is shown in FIGS. 1 through 5, and illustrative crosssectional views are shown in FIGS. 5 through 9.

As shown in FIGS. 1 through 5, the embodiment of the present invention1000 can be constructed of these subassemblies to provide a patch-like,wearable, self-contained substance infusion device that can be used todeliver a variety of medications to a patient. The device 1000, shown ina pre-energized, pre-activated position in FIG. 1, provides a hiddenpatient needle or needles prior to and during use, and can be secured toa patient via an adhesive surface. The pressurization of the contents ofthe reservoir can be achieved by removing the pull handle 260 to“energize” the device and device contents, and the device can then be“activated” via a reasonable force applied to the push-button 360 toseat the patient needles and establish a flow path between the reservoirand needles. In doing so, the device 1000 facilitates self-injection andreduces or eliminates variations in injection techniques between users.

FIG. 1 is a top perspective view of a first embodiment of the infusiondevice 1000. In FIG. 1, the assembled upper and lower housing 110 and210 respectively is shown, between which the push button subassembly 300is contained. The pull handle 260, described in greater detail below, isshown in a pre-energized, pre-activated position and serves to securethe retaining pin 140 within the device and shield the push button 360from any applied forces. As more clearly illustrated in FIG. 2, which isa bottom perspective view of the first embodiment, the pull handle 260is further interlocked with the needle cap 240 and the retaining pin 140via clip 270. Also, as illustrated in FIG. 6, which is a cross-sectionalview (6-6 in FIG. 1) of the first embodiment, the pull handle 260 isfurther interlocked with the push button slide 320. A top view of thefirst embodiment shown in FIG. 3 illustrates the alignment and travelbetween the push button slide 320 and the device, which is required foractivation. FIG. 4 is a side elevational view of the first embodimentand illustrates the low profile of the device and the centeredpositioning of the patient needle opening, which is more clearlyillustrated in the bottom view of the first embodiment shown in FIG. 5.

FIGS. 6 through 9, and FIG. 11A through 11C, illustrate a number ofcross-sectional views (6-6 in FIG. 1) of the first embodiment andillustrate the construction, positioning and operation of eachsubassembly in a pre-energized, pre-activated position, and subsequentpost-energized and post-activated positions, each described in greaterdetail in separate sections below.

Reservoir Subassembly

In FIG. 10A, the reservoir subassembly 100 of the infusion device 1000is shown, and can be comprised of a rigid portion 120 used inconjunction with one or more non-distensible but flexible films 170,such as metallized films. The reservoir subassembly 100 can contain anynumber of substances between either a first and second film, whereeither the first or second film is also positioned against the rigidportion, or between a first film and the rigid portion.

The rigid portion 120, or reservoir base, can be comprised of and serveas a hard portion of the reservoir against which the flexible film 170can be pressed as described in greater detail below. As shown moreclearly in FIG. 6, the rigid portion 120 can contain a dished outcentral section 122 and a flange 124, provided about the perimeter ofthe rigid portion to allow for heat sealing the flexible film 170, orfilm lid, to the rigid portion and to form a content reservoir, orchamber, therebetween. The reservoir subassembly of FIG. 10A can furtherprovide a guide opening 112 for mateably receiving a guide 126 forprecise positioning and attachment between the rigid portion 120 and theupper housing 110 using any number of techniques, such as ultrasonicstaking.

As noted above, the reservoir of the embodiment shown in FIG. 10A can beconstructed to preferably have a hard shell or inner surface, and atleast one flexible film attached about the perimeter of the hard shellor inner surface. The flexible film 170 can be heat sealed to the rigidportion 120 to create a chamber, or bladder, for storage of devicecontents. As at least one wall of the chamber comprises a flexible film170, and at least one wall of the chamber comprises a rigid surface, oneor more Belleville springs 130 can be placed adjacent to the flexiblefilm 170 and used to apply a substantially constant pressure to theflexible film 170, and pressurize the reservoir chamber and contents.

As shown in FIGS. 6 and 10A, a Belleville spring 130 is provided toapply a substantially even and constant pressure to the flexible film170 of the reservoir subassembly 100, compressing the contents of thereservoir between the flexible film 170 and the rigid portion 120, andforcing the contents from the reservoir through one or more flow pathsas shown in greater detail in FIG. 12, which illustrates a partialcross-sectional view of the fluid path and reservoir subassembly of FIG.10A. As noted above, the reservoir of FIG. 10A can also be made up oftwo or more flexible, non-distensible films, wherein the contents can becontained between the films where at least one film is attached to therigid portion 120 to provide a rigid base for compressing andpressurizing the contents of the reservoir. In yet another embodiment ofthe reservoir subassembly 100, the flow rate is automatically adjustedfrom an initial high rate to one or more stepped-down lower flow rates.Additional details of an adjusting flow rate are further discussed inU.S. patent application Ser. No. 10/396,719, entitled “Multi-Stage FluidDelivery Device And Method”, filed on Mar. 26, 2003, the entire contentof which is incorporated herein by reference.

The flexible film 170 of the reservoir subassembly 100 can be made ofnon-distensible materials or laminates, such as metal-coated films orother similar substances. For example, one possible flexible laminatefilm which can be used in the reservoir subassembly 100 of the firstembodiment can be comprised of a first polyethylene layer, a secondchemical layer as known to those skilled in the art to provide anattachment mechanism for a third metal layer, which is chosen based uponbarrier characteristics, and followed by a fourth layer comprised ofeither polyester or nylon. By utilizing a metal-coated or metallizedfilm 170 in conjunction with a rigid portion 120, the barrier propertiesof the reservoir are improved, thereby increasing or improving the shelflife of the contents contained within. For example, where a reservoircontent includes insulin, the primary materials of contact in thereservoir subassembly 100 of the embodiment described above includelinear, low-density polyethylene (LLDPE), low-density polyethylene(LDPE), cyclic olefin copolymer (COC) and Teflon. As described ingreater detail below, the primary materials of contact in the remainingflow path of the reservoir contents include polyethylene (PE), medicalgrade acrylic, and stainless steel. Such materials which are in extendedcontact with the contents of the reservoir subassembly preferably passISO 10-993 and other applicable biocompatibility testing.

The reservoir of the reservoir subassembly 100 is further preferablyable to be stored for the prescribed shelf life of the reservoircontents in applicable controlled environments without adverse effect tothe contents and is capable of applications in a variety ofenvironmental conditions. Additionally, the barrier provided by thecomponents of the reservoir do not permit the transport of gas, liquidand solid materials into or out of the contents at a rate greater thanthat allowable to meet the desired shelf life. In the embodiment shownin FIG. 10A, the reservoir subassembly materials are capable of beingstored and operated in a temperature range of approximately 34 to 120degrees F., and can have a shelf life of two or more years. For example,as shown in FIG. 13, the reservoir subassembly as described above has noimpact on insulin stability during use with the device. FIG. 13 is aplot illustrating an example of insulin stability data for the reservoirsubassembly of FIG. 10A.

In FIG. 13, the insulin stability of reservoir contents, which isplotted as insulin concentration levels along the Y axis, is shown for 6insulin containing devices over a storage period of 25 (or more) days.The compared devices include the first embodiment of the presentinvention having a 4 CC reservoir, a 25 CC reservoir, and a 37 CCreservoir, as well as a 4 CC, 25 CC, and 37 CC glass vial insulincontaining device. As shown in FIG. 13, the insulin concentration instability samples varies very little over the 25 day period, and littleor no difference is noted between plots for each device over the sameperiod. In addition to satisfying stability requirements, the reservoircan further ensure operation by successfully passing any number of leaktests, such as holding a 30 psi sample for 20 minutes without leaking.Additional filling, storage and delivery benefits resulting from theconfiguration of the reservoir subassembly include minimized headspaceand adaptability as described in greater detail below.

The reservoir of the reservoir subassembly 100 is preferably evacuatedprior to filling, as described in greater detail below. By evacuatingthe reservoir of FIG. 10A prior to filling, and having only a slightdepression 122 in the hard floor of the rigid portion 120, headspace andexcess waste within the reservoir can be minimized. In addition, theshape of the reservoir may be configured to adapt to the type ofenergizing mechanism used, e.g., a disk or Belleville spring 130 havingany number of diameter and height dimensions. Additionally, using anevacuated flexible reservoir during filling minimizes any air or bubbleswithin the filled reservoir. The use of a flexible reservoir is alsovery beneficial when the device is subjected to external pressure ortemperature variations, which can lead to increased internal reservoirpressures. In such case, the flexible reservoir expands and contractswith the contents, thereby preventing possible leaks due to expansionand contraction forces exerted on the fill plug 150 and septum 160. Thisalso helps to eliminate dose variation due to temperature and pressurefluctuations in the environment.

As noted above, the small depression 122 located on the surface of therigid portion 120 helps to inhibit the formation of fluid retainingpockets as the reservoir film 170 collapses under the pressure of theBelleville spring 130. This depression also assists in filling thereservoir system by providing a fluid flow path since it is preferableto evacuate the system prior to introducing fluid into it. Thisintroduction of fluid can be accomplished at the time the device ismanufactured, or right up to the time it is to be used by the end user.For example, in one filling method the reservoir can be evacuated,filled via the fill port 152, then provided a fill plug 150.Alternatively in a second filling method, the reservoir can beevacuated, then provided a fill plug 150, and later filled through thefill plug 150 prior to use. This allows the reservoir of the device tobe received at a drug filling location in such a manner as to allow foraseptic filling with low headspace and a sterility-maintainingconnection of fluid flow paths. As described in greater detail below,any reservoir access needles and patient needles can also be capped inthis sterility-maintaining manner.

Yet another feature of the reservoir subassembly 100 includes theability to permit automated particulate inspection at the time of fill,or by a user at the time of use. One or more reservoir barriers, such asthe rigid portion 120, can be molded of a transparent, clear plasticmaterial, which allows inspection of the substance contained within thereservoir. The transparent, clear plastic material is preferably acyclic olefin copolymer that is characterized by high transparency andclarity, low extractables and biocompatibility with the substancecontained in the reservoir. A suitable material is available from ZeonChemicals, L.P., of Louisville, Ky. under the designation “BD CCPResin”, and is listed by the U.S. Food and Drug Administration as DMFNo. 16368. In such applications, the reservoir includes minimal featureswhich could possibly obstruct inspection (i.e. rotation duringinspection is permitted).

Fluid Path

The rigid portion 120 of the reservoir subassembly 100 of FIG. 10Afurther comprises at least one a fluid path 128 as shown in FIG. 12,which accesses the main chamber 127 of the reservoir. In the embodimentshown in FIG. 12, the fluid path 128 exits the main chamber 127 of thereservoir, passing under or through the heat seal area provided aboutthe perimeter of the rigid portion 120 for securing the flexible film170, and into a chamber 129 between a fill-head stopper 150 and a septum160, allowing fluid of the reservoir to travel from the reservoir to theseptum 160. In the embodiment shown in FIG. 12, the fluid path 128 ispreferably constructed to reduce dead volume and incorporates thefill-head receiving geometry as described in greater detail below.

The fluid path 128 is constructed of materials similar or identical tothose described above for the reservoir subassembly, and that satisfynumerous biocompatibility and storage tests. For example, as shown inTable 1 below, where the device content includes insulin, the primarymaterials of contact in the reservoir subassembly 100 of the embodimentincludes linear, low-density polyethylene, cyclic olefin copolymer andTeflon, and can also include a transparent, clear plastic. The primarymaterials of contact in the remaining flow path between the reservoirsubassembly and the microneedles 222 of the patient needle manifold 220include polyethylene, medical grade acrylic, and/or stainless steel.

TABLE 1 Path Component Material Reservoir Polyethylene, cyclic olefincopolymer and/or Teflon Reservoir Film metal-coated film, such aspolyethylene, aluminum, polyester and/or nylon with a chemical tielayer, such as the product A83, manufactured by Beacon Converters ofSaddle Brook N.J. Septum Halo-butyl rubber Septum Needle Stainless steelSeptum Needle Manifold Polyethylene and/or medical grade acrylic TubePolyethylene with a PVC outer layer and a Ethyl Vinyl Acetate tie layerPatient Needle Manifold Polyethylene and/or medical grade acrylicPatient Needle Manifold Film Polyester, aluminum and a sealant layer,such as the product A40, manufactured by Beacon Converters of SaddleBrook N.J. Patient Needle Stainless steel

Specifically, the patient and septum needles 222 and 330 respectively,can be constructed of stainless steel, the septum needle manifold 322and patient needle manifold 220 can be constructed of polyethyleneand/or medical grade acrylic, the septum 160 can be constructed ofhalo-butyl rubber, and the flexible tube 350 between the septum needleand/or the septum needle manifold and the patient needle manifold can beconstructed of polyethylene with a PVC outer layer and a Ethyl VinylAcetate tie layer. Such materials when in extended contact with thecontents of the reservoir subassembly preferably pass ISO 10-993biocompatibility testing.

The septum 160 of FIG. 10A, is positioned between the first fluid path128 and a second fluid path comprised of the septum needle 330, septumneedle manifold 322, and tube 350, and can be an elastomeric plug thatwhen penetrated by a septum spike or septum needle 330, creates asterile flow path between the reservoir and the patient needles 222. Theseptum needle 330, which is used to penetrate the septum 160 and createa flow path between the first and second fluid paths, can include aseptum needle boot 340 that maintains the sterility of the septum needleprior to, and after the boot is collapsed and the fluid path is created.

As described in greater detail below, the septum needle 330 can besignificantly larger than the patient needles 222, such as 25-29 gauge,to allow easier handling and preventing flow restriction. As moreclearly shown in FIGS. 10C and 12, the septum needle boot 340, orsheath, is sized to engage a recess opening 342 provided by the septumelastomeric plug 160 prior to being pierced by the septum needle 330.This engagement between the septum needle boot 340 and the recessopening 342 provided by the septum elastomeric plug 160 creates asterile environment through which the septum needle 330 travels whenpiercing the septum needle boot and septum, such that at no time is theseptum needle exposed to a non-sterile environment.

Fill Head Port

Returning to FIGS. 10A and 12, the chamber 129 between the septum 160and reservoir can also be accessed through a fill-head port 152 locatedin the reservoir subassembly 100 which can be closed with a fill-headstopper 150. The fill-head stopper 150 and septum 160 can be identicalparts, which further reduces manufacturing complexity.

Through the use of the fill-head port 152, the device can allow fillingof the reservoir from an external source even after complete assemblyand/or at the point of use. In a first fill method, a completed, fullyassembled device can be provided without a fill plug 150 in place in thefill-head port 152, and the fill plug, or fill-head stopper, can then beadded after filling the reservoir with a filler device. Alternatively ina second fill method, a completed, fully assembled, yet unfilled devicecan be provided with the fill-head stopper 150 in place in the fill-headport 152, and then filled by injecting through the fill-head stopperusing a standard syringe or similar device. Since the top of thereservoir can be made of a clear material, fill levels and excess aircan be easily seen and withdrawn using the same syringe. In this way,careful control of fill volume and dose delivery can be maintained.

For infusor devices which are pre-filled, the fill-head port 152 isprovided with the fill-head stopper 150 which closes the fill-head port.The upper housing 110 can then be used to hold the fill-head stopper 150in place and prevent the stopper from backing out while also providingaccess to the fill-head stopper for filling where desired. For infusordevices which allow filling at the time of use, the fill-head port 152can remain accessible, either through the fill-head stopper 150 asdescribed above, or through an inner collar beyond the removed fill-headstopper. In each filling application, the fill-head port 152 allowsfluid to travel from an external source via the fluid path 128 describedabove, into the main chamber 127 of the reservoir subassembly 100, whichcan further include input and output ports to aid in filling.

Where filling at the time of use is to occur, the device does notrequire the activation steps outlined in detail below. When the deviceis to be filled at the time of use, the Belleville spring 130 is notrequired to be held in a retracted position by a retaining pin 140, aspressure applied to the empty reservoir by the released Bellevillespring will have no effect. Filling the device at the time of use servesto displace the Belleville spring 130, which is free to press thereservoir subassembly and force contents from the reservoir once theexternal filling pressure source is removed from communication with thereservoir. Additionally, such filling at the time of use allows sterilepackaging steps without the restrictions presented by a devicecontaining a medication.

Belleville Spring

As shown in FIG. 10A, a disk or Belleville spring 130 is included in thedevice 1000 for applying an essentially even, constant force to thereservoir to force the contents from the reservoir, and is hereinaftersometimes referred to as a “constant force spring”. The constant forcespring 130 is used to store energy that, when released by deviceactivation, pressurizes the reservoir at the time of use. The spring 130is held in a flexed state by a pin 140 positioned at the center of aplurality of spring fingers. In doing so, the spring is prevented fromputting stress on the film 170 of the reservoir subassembly 100 or anyremaining device components during storage.

The pin 140, or retaining pin, can be any suitable pin, tube or ring,that is sufficiently rigid to resist spring tension and deformation, andsecure the pin to a removal mechanism, such as a pull handle 260described in greater detail below. The pin 140 should not fail undernormal tensile load or, if part of an assembly, should not disassembleat forces that can be induced by shipping and handling, and resulting ininadvertent activation.

In FIG. 10B, a pull handle 260 is provided to aid in the removal of theretaining pin 140 described above. The pull handle 260 is positionedadjacent to the bottom surface of the device, and includes one or moremembers which extend to one side of the device creating a mechanicaladvantage for the removal of the retaining pin 140. In the embodimentshown in FIG. 10B, the pull handle 260 includes a member 262 thatextends and shields the button head 360 of the push button subassembly300. In doing so, the pull handle 260 prevents the application of aforce to the push button 360 until the pull handle is removed. Thisprevents accidental activation of the device via the push button priorto proper placement.

In the embodiment described above, the pull handle 260 includes a memberwhich prevents the application of a force to the push button. In otherversions of this embodiment, the pull handle can include a member whichextends between the push button and the device housing to preventmovement of the push button when a force is applied to the push button.

Still other pull handle/push button interlocks can be provided betweenthe pull handle 260 and the needle cap 240 and the retaining pin 140,ensuring proper operation and preventing accidental activation. Forexample, in FIG. 10B, the pull handle 260 also includes members 264 thatextend from the pull handle surface into openings in the push buttonslide 320 and prevents the application of a force to the push button 360from moving the slide until the pull handle has been removed, activatingthe device.

In yet another version of the embodiment described above, the pushbutton and button slide itself can serve to release the retaining pin.In this version, as the push button is activated, the retaining pin isskewed from a substantially perpendicular position relative to theBelleville spring. As the retaining pin is skewed further and further,the retaining pin is eventually released from the Belleville spring.Removal of the pull handle 260 can also include a tactile and audibleindicator providing user feedback.

When the retaining pin 140 is pulled free of the Belleville spring 130,the fingers of the spring drop, and in doing so, exert a force on thefilm lid 170 of the reservoir subassembly 100. The edge of the spring130 is trapped between the reservoir and the upper housing, and can beconfigured to preferably create a pressure within the reservoir of fromabout 1 to 50 psi, and more preferably from about 2 to about 25 psi, andmost preferably from about 15 to about 20 psi for intradermal deliveryof the reservoir contents. For sub-cutaneous injection or infusion, arange of about 2 to 5 psi may be sufficient.

The Belleville spring can be sized between about 1.15 to 1.50 inches indiameter, preferably 1.26 inches, to allow for a full 600 μl delivery.As shown in FIG. 14, a commonly found Belleville spring calculationgraph as known to those skilled in the art can be used to calculate anoptimum spring geometry. As shown in FIG. 14, multiple plots show loaddeflection characteristics for Belleville washers of differentheight-to-thickness ratios. As known to those skilled in the art, aBelleville washer, or Belleville spring, exhibits a load characteristic,shown as a percentage of flat position load deflection, as the springtravels from a flat or flexed state to a relaxed state. As shown in FIG.14, the selection of a spring having a specific height to thicknessratio can be used to create a desired load deflection profile.

Housing Subassembly

Returning to FIG. 10B, a bottom, or lower housing 210 is provided thatcan mate with the upper housing 110 and the reservoir subassembly 100described above. The lower housing 210 can be used to trap and containall remaining components, and can provide snap features to receive andattach components and housing members. The lower housing 210 can alsoinclude one or more guiding features for securing, releasing, anddirecting the button slide 320 and patient needle manifold 220 asdescribed in greater detail below. A break line between units, such asbetween the upper and lower housing units, can be positioned towardvertical center of the device, which creates a more stable assemblysince the push button subassembly described below can be top down loadedinto a substantial housing instead of onto a plate. The upper and lowerhousings 110 and 210 respectively, can then be snap fit or bondedultrasonically to one another.

The upper and lower housings 110 and 210 respectively further allow theuse of independent subassembly components, where each component can beself contained and stable. For example, the assembled and separatereservoir, specifically the reservoir base surface 120, fill plug 150,septum 160 and reservoir film 170 of the reservoir subassembly 100,contains no unnecessary parts and as a result brings a low particle loadinto filling operations. In addition, all stored energy components canbe contained separate from the reservoir so they cannot be inadvertentlydeployed during filling

Microneedles

Returning to FIGS. 10B and 10C, the disclosed device also contains atleast one patient needle 222, or microneedle, but may contain several,such as the three microneedles shown in the push button subassembly 300of FIG. 10C. Each microneedle 222 is preferably at least 31 gauge orsmaller, such as 34 gauge, and is anchored within a patient needlemanifold 220 which can be placed in fluid communication with thereservoir. Each microneedle is secured to prevent disassembly from themanifold 220 at any force less than 1 pound. The microneedles 222, whenmore than one is included in the device, may also be of differinglengths, or gauges, or a combination of both differing lengths andgauges, and can contain one or more ports along a body length,preferably located near the tip of the needle or near the tip bevel ifthe needle has one.

In the embodiment described above, the use of multiple 34 gauge needlesto deliver the reservoir contents is practical as the infusion occursover a longer period than typically associated with an immediate syringeinjection requiring a much larger cannula, or needle. In the disclosedembodiments, any microneedle can be used which targets either theintradermal or subcutaneous space; however, the embodiment shown in FIG.10C includes microneedles of between 1 and 4 mm in exposed length (i.e.,2 mm), and the arrangement of these patient needles can be in a linearor nonlinear array, and can include any number of needles as required bythe specific application.

Push Button Subassembly

In FIG. 10C, a push button subassembly 300 is shown and integrates aseptum needle 330, septum needle manifold 322, and push button slide 320into one piece; however, fabrication of the push button subassembly 300can be simplified somewhat by providing a snap-on push button face plate360 to allow for two or more simpler molded button parts. The pushbutton slide 320 also provides a mechanism to secure the patient needlemanifold in a retracted position, and release the manifold when thedevice is properly activated.

As shown in FIG. 10C, tubing 350 which is used to establish a fluid pathas described in greater detail below exits the septum needle manifold322 on the same side as a tubing entry to the patient needle manifold220 allowing easier assembly and creating a flexible fluid path betweenthe septum needle manifold and the patient needle manifold. The patientneedle manifold 220 containing the patient needles 222 is assembled intotracks 324 provided by the button slide 320 and creates a stablesecuring and release mechanism, as described in greater detail below.

As shown in FIG. 10C, a pair of detents 326 and 328 can be providedalong the tracks 324 to hold the button slide 320 in place at variousstages or positions. For example the button subassembly 300 of FIG. 10Cprovides multiple positions to allow for reservoir loading, patientneedle and septum needle manifold assembly, housing welding and useractivation. Specifically, at least three positions are provided.

A first position, or assembly position, is provided for reservoirloading and house welding. As the patient needle manifold 220 is heldstationary relative to the slidable movement of the button slide 320,the first position is provided wherein the grooves 221 of the patientneedle manifold engage the first set of detents 326 of the button slide320. In this position, loading can occur without interference betweenthe septum boot 340 and the septum 160.

A second position, or ship position, is provided for shipment andestablishes the septum needle boot 340 and septum 160 seal. As thepatient needle manifold 220 remains stationary relative to the slidablemovement of the button slide 320, the second position is provided as thebutton slide is slidably engaged and the grooves 221 of the patientneedle manifold disengage from the first set of detents 326, remainingpositioned within the tracks 324, and then engage the second set ofdetents 328 of the button slide 320. In this position, the septum needleboot 340 engages a recess opening 342 provided by the septum elastomericplug 160 prior to being pierced by the septum needle 330. Thisengagement between septum needle boot and the recess opening creates asterile environment through which the septum needle travels whenpiercing both the septum needle boot and septum. Therefore at no time isthe septum needle 330 exposed to a non-sterile environment, and thiseffectively eliminates the effects of minor far field welding.

A third position is provided as an activated, or in-use position. As thepatient needle manifold 220 remains stationary relative to the slidablemovement of the button slide 320, the third position is provided as thebutton slide is slidably engaged and the grooves 221 of the patientneedle manifold disengage from the second set of detents 326, remainingpositioned within the tracks 324 until aligned with the track opening325, then falling free of the button slide 320. In this third position,the septum 160 is penetrated, and the manifold and safety mechanism,both described in greater detail below, are released and forced downwardtowards the user's skin surface, driven by the spring 310. In theembodiment shown, the force required to penetrate the septum 160,compress the septum needle boot 340 and release the patient needlemanifold 220, in moving to this third position is typically between 2and 4 pounds.

The patient needle and septum needle manifold assemblies 220 and 322respectively, enable access and discharge of fluid contained within thereservoir and delivery of the fluid to the patient needles 222. Eachmanifold housing therefore contains a number of fluid flow paths forrouting reservoir contents received from the septum needle 330, or otherprotuberance, and any associated tubing 350, and delivering the contentsto the patient needles 222 and into the skin of the user. The patientneedle manifold 220 in which the patient needles 222 are anchored is influid communication with the septum needle manifold 322, in which theseptum needle 330 is anchored, by way of a flexible tubing 350.

The patient needle manifold 220 is held in a pre-release, or “up” state,under load, provided by one or more springs 310, by the push buttonsubassembly 300 and lower housing 210. In the first version of securingthe patient needle manifold 220 in an up state described above, thepatient needle manifold 220 slidably engages a set of tracks 324disposed on the button slide 320. As the patient needle manifold 220remains stationary within a chute 212 provided by the lower housing 210,the button slide 320 slidably travels until a track opening 325 alignswith the patient needle manifold 220, releasing the patient needlemanifold 220 from the tracks 324 within the chute.

In a second version of securing the patient needle manifold 220 in an upstate, one or more protruding blocks (not shown) extend from the buttonslide 320 and hold the needle manifold 220 in an up state, under load,provided by one or more springs 310. During activation, the button slide320 is slidably displaced, moving the blocks free of the patient needlemanifold 220 which is released and travels toward the skin surface ofthe user, guided along a travel path by features in the lower housing210 and the button slide 320. As the blocks move free of the patientneedle manifold 220, the manifold drops and the needles 222 seat in theuser's skin. Additional details of supporting blocks are furtherdiscussed in U.S. patent application Ser. No. 60/420,233, referencedabove, the entire content of which is incorporated herein by reference.

In each version described above, one or more drive springs 310 exert aforce on the top of the patient needle manifold 220 to drive themanifold when activated, or released from the up state, allowing forpatient needle 222 seating when the manifold is released, and creating afluid path between the septum needle, septum needle manifold, flexibletubing, patient needle manifold and the array of patient needles. Thedrive springs 310 serve to “plant” the needles into the skin via thespring-loaded patient needle manifold 220 which can travel at a speedranging between 15 and 26 miles per hour (between 6 and 12 meters persecond)

The slidable motion of the button slide 320 also pushes the septumneedle 330 through the septum needle boot 340 and the septum 160,creating a flow path between the reservoir and the septum needle. Aseptum needle containing manifold 322 can be attached or constructed asa component of the button slide 320, and moves with the button slideduring activation steps until the septum needle 330 penetrates theseptum boot 340, and subsequently the septum 160. Depending upon thesequence desired, prior to, concurrent with, or slightly after theseptum needle 330 penetrates the septum 160, the patient needle manifold220 is released and bottoms out against the skin surface, seating thepatient needles 222 and thereby initiating flow of energized fluid fromthe reservoir, through the septum needle and septum needle manifold,through the flexible tubing attached to the septum needle manifold, andto the patient needles of the patient needle manifold.

One or more septum needles 330 can be provided, separate from thepatient microneedles 222, allowing greater flow within the completefluid path between reservoir and patient needles. In the embodimentdescribed above, the complete fluid path includes in part, two or moreneedles, specifically, at least one septum needle 330, and at least onepatient microneedle 222. This allows the device to incorporate needlesof different constructions depending upon the fluid path characteristicsdesired. For example, the patient microneedles 222 can include one ormore 34 gauge needles, where the septum needle 330 can include one ormore equal or larger needles as required. Additionally, the separationof the patient and septum needles allows further freedom of movement ofthe patient needles during operation of the device.

A flexible tube 350 can be used to connect the septum needle 330 and/orseptum needle manifold 322 to the patient needle manifold 220. Theflexible nature of the tube coupling allows the patient needle manifold220 to move with greater independence from the remaining components ofthe device, allowing more effective needle seating. Once properlyseated, the patient needle manifold 220 completes the fluid path betweenthe flexible tubing 350 and the array of patient microneedles 222, andthe user's skin. As noted above, the patient needle manifold 220 isguided into position by features in the lower housing 210, and the drivesprings 310 described above exert a force on top of the patient needlemanifold 220 allowing for needle seating when the manifold is released.A variety of drive spring options exist, including the use of as few asone or as many as four coil springs, or one or more leaf springs.

A detailed embodiment of the patient needle manifold 220 is shown inFIGS. 15A and 15B. FIG. 15A is a perspective view of a preferredembodiment of the patient needle manifold patient contact surfaceconfiguration for the patient needle manifold 220, and FIG. 15B is aperspective view of second patient contact surface configuration.Additional details of manifolds are disclosed in a commonly-assignedU.S. patent application of Alex Lastovich et al., Ser. No. 10/357,502,filed on Feb. 4, 2003 and entitled “Device And Method For Delivering OrWithdrawing A Substance Through The Skin”, the entire content of whichis incorporated herein by reference and in U.S. patent application Ser.No. 60/447,359, Ser. No. 60/450,680, and Ser. No. 60/450,681, referencedabove, the entire contents of each being incorporated herein byreference.

In the patient needle manifold embodiment shown in FIGS. 10C and 15, atleast one fluid communication path, or feed channel, is provided to eachpatient needle 222. The manifold may simply have a single path to one ormore patient needles, or may provide multiple fluid paths or channelsrouting contents to each needle separately. These paths or channels mayfurther comprise a tortuous path for the contents to travel, therebyaffecting fluid pressures and rates of delivery, and acting as a flowrestrictor. The channels or paths within the patient needle manifold 220can range in width, depth and configuration depending upon application,where channel widths are typically between about 0.015 and 0.04 inch,preferably 0.02 inch, and are constructed to minimize dead space withinthe manifold. As further shown in FIG. 1C, the patient needle manifold220 can also include a film lid 224, comprised of materials outlined inTable 1, to seal the manifold and exposed manifold channels. As with thefluid path analysis above and outlined in Table 1, the film lid 224material is also chosen to be fully compatible with the contents of thedevice, and provide minimal extractables resulting in fewerparticulates. In yet other embodiments of the patient needle manifold,the manifold can be non-film sealed, such as where the manifold includesenclosed channels within the manifold body.

The skin contact surface of the patient needle manifold 220 shown inFIG. 15A shows a skin contact surface having a plurality of exposedneedles, with each needle extending from a needle cone 226. Each needlecone 226 can include, or be placed adjacent to one or more glue wells228 provided to allow attachment between the patient needle 222 and thepatient needle manifold 220. As illustrated in FIG. 15A, each patientneedle cone 226 is preferably not uniform about the entire conecircumference and can include a removed portion of the needle cone ofvariable size and depth. Such a segment or cut-out section of thepatient needle cone 226 can be removed to create a glue well 228, orprovide laser weld access, to secure each needle within the needle coneat the required height with minimal intrusion into the flow paths of themanifold.

A second version of the skin contact surface of the patient needlemanifold 220 is shown in FIG. 15B (contact surface shown only). Theneedle cones of FIG. 15B include a removed cone section both above andbelow the patient contact surface, positioned as described for theversion in FIG. 15A. However, in the version shown in FIG. 15B, atapered recess is also provided extending below the removed portion ofthe patient needle cone, adjacent to the needle opening. Therefore, asshown in FIG. 15A, the removed portion can be merely a removed segmentof the cone circumference above the patient contact surface, or as shownin FIG. 15B, a larger segment of the cone circumference can be removed,which is then further extended into the manifold surface to provide amore extensive glue well.

The removed portion and adjacent recess described above can be used toaid in front gluing the patient needles 222 within the patient needlemanifold 220 during manufacture, and can facilitate other types offixing such as laser welding. Such a front glue method allows areduction in height of the chamber within the manifold in which theblunt end of the needle 222 is positioned, and further prevents gluefrom depositing in and around the fluid path within the manifold. Theundesired introduction of glue into these fluid paths can createproblems in glue/drug interactions, as well as creating unknown orvariable dead volumes within the patient needle manifold 220 itself. Theuse of front gluing further provides a greater degree of repeatability,allowing accurate calculations of any minor glue-caused dead volumesthat do occur. However, such glue positioning upon the patient contactsurfaces shown in FIGS. 15A and 15B should preferably be carefullymonitored to prevent glue domes about the needle bases, which can reduceexposed needle length.

The subassembly embodiments presented above are not restrictive, and canbe reconfigured as required in a given application. For example, anotherembodiment of the subassemblies described above are shown in FIGS. 16Athrough 16B. FIG. 16A is a top perspective view of another embodiment ofthe subassemblies of FIGS. 10A through 10C partially assembled, andFIGS. 16B and 16C are cross-sectionals view of the subassemblies shownin FIG. 16A prior to, and after energizing and activation, respectively.As shown in FIG. 16A, the lower housing 180 can be configured toslidably receive a one piece push button slide 182 having a septumneedle 184 similar to the button slide assembly 320 described above. Awider patient needle manifold 186 having at least one patient needle(not shown) can also be included, extending parallel to the button slidetravel and including a first and second drive spring 188. In thesubassembly embodiment shown in FIG. 16A, the septum needle 184 andpatient needle manifold remain in fluid communication via a flexibletubing 190 substantially as described above, allowing the patient needlemanifold to travel free of restrictions once released, as shown in FIG.16C.

The engagement of the button slide assembly 320 within the lower housing180 in the embodiment shown in FIGS. 16A through 16C further provides anoverall lower device profile, in addition to improving handling andmanufacturing requirements. The flexible tubing 190 is more readilyconformed in this embodiment, and allows a more simplified push buttonslide.

Operation

The device described above is suitable for use in administering varioussubstances, including medications and pharmaceutical agents, to apatient, and particularly to a human patient. As used herein, apharmaceutical agent includes a substance having biological activitythat can be delivered through the body membranes and surfaces, andparticularly the skin. Examples, listed in greater detail below, includeantibiotics, antiviral agents, analgesics, anesthetics, anorexics,antiarthritics, antidepressants, antihistamines, anti-inflammatoryagents, antineoplastic agents, vaccines, including DNA vaccines, and thelike. Other substances that can be delivered intradermally orsubcutaneously to a patient include human growth hormone, insulin,proteins, peptides and fragments thereof. The proteins and peptides canbe naturally occurring, synthesized or recombinantly produced.Additionally, the device can be used in cell therapy, as duringintradermal infusion of dendritic cells.

Still other substances which can be delivered in accordance with thepresent invention are drugs, vaccines and the like used in theprevention, diagnosis, alleviation, treatment, or cure of disease, withthe drugs including Alpha-1 anti-trypsin, Anti-Angiogenesis agents,Antisense, butorphanol, Calcitonin and analogs, Ceredase, COX-IIinhibitors, dermatological agents, dihydroergotamine, Dopamine agonistsand antagonists, Enkephalins and other opioid peptides, Epidermal growthfactors, Erythropoietin and analogs, Follicle stimulating hormone,G-CSF, Glucagon, GM-CSF, granisetron, Growth hormone and analogs(including growth hormone releasing hormone), Growth hormoneantagonists, Hirudin and Hirudin analogs such as hirulog, IgEsuppressors, Insulin, insulinotropin and analogs, Insulin-like growthfactors, Interferons, Interleukins, Leutenizing hormone, Leutenizinghormone releasing hormone and analogs, Low molecular weight heparin,M-CSF, metoclopramide, Midazolam, Monoclonal antibodies, Narcoticanalgesics, nicotine, Non-steroid anti-inflammatory agents,Oligosaccharides, ondansetron, Parathyroid hormone and analogs,Parathyroid hormone antagonists, Prostaglandin antagonists,Prostaglandins, Recombinant soluble receptors, scopolamine, Serotoninagonists and antagonists, Sildenafil, Terbutaline, Thrombolytics, Tissueplasminogen activators, TNF—, and TNF—antagonist, the vaccines, with orwithout carriers/adjuvants, including prophylactics and therapeuticantigens (including but not limited to subunit protein, peptide andpolysaccharide, polysaccharide conjugates, toxoids, genetic basedvaccines, live attenuated, reassortant, inactivated, whole cells, viraland bacterial vectors) in connection with, addiction, arthritis,cholera, cocaine addiction, diphtheria, tetanus, HIB, Lyme disease,meningococcus, measles, mumps, rubella, varicella, yellow fever,Respiratory syncytial virus, tick borne japanese encephalitis,pneumococcus, streptococcus, typhoid, influenza, hepatitis, includinghepatitis A, B, C and E, otitis media, rabies, polio, HIV,parainfluenza, rotavirus, Epstein Barr Virus, CMV, chlamydia,non-typeable haemophilus, moraxella catarrhalis, human papilloma virus,tuberculosis including BCG, gonorrhoea, asthma, atheroschlerosismalaria, E-coli, Alzheimers, H. Pylori, salmonella, diabetes, cancer,herpes simplex, human papilloma and the like other substances includingall of the major therapeutics such as agents for the common cold,Anti-addiction, anti-allergy, anti-emetics, anti-obesity,antiosteoporeteic, anti-infectives, analgesics, anesthetics, anorexics,antiarthritics, antiasthmatic agents, anticonvulsants, anti-depressants,antidiabetic agents, antihistamines, anti-inflammatory agents,antimigraine preparations, antimotion sickness preparations,antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics,antipsychotics, antipyretics, anticholinergics, benzodiazepineantagonists, vasodilators, including general, coronary, peripheral andcerebral, bone stimulating agents, central nervous system stimulants,hormones, hypnotics, immunosuppressives, muscle relaxants,parasympatholytics, parasympathomimetrics, prostaglandins, proteins,peptides, polypeptides and other macromolecules, psychostimulants,sedatives, sexual hypofunction and tranquilizers and major diagnosticssuch as tuberculin and other hypersensitivity agents as described inU.S. Pat. No. 6,569,143, entitled “Method Of Intradermally InjectingSubstances”, the entire content of which is incorporated herein byreference.

Vaccine formulations which can be delivered in accordance with thepresent invention can be selected from the group consisting of anantigen or antigenic composition capable of eliciting an immune responseagainst a human pathogen, which antigen or antigenic composition isderived from HIV-1, (such as tat, nef, gp120 or gp160), human herpesviruses (HSV), such as gD or derivatives thereof or Immediate Earlyprotein such as ICP27 from HSVI or HSV2, cytomegalovirus (CMV (espHuman) (such as gB or derivatives thereof), Rotavirus (includinglive-attenuated viruses), Epstein Barr virus (such as gp350 orderivatives thereof), Varicella Zoster Virus (VZV, such as gp1, II andIE63) or from a hepatitis virus such as hepatitis B virus (for exampleHepatitis B Surface antigen or a derivative thereof), hepatitis A virus(HAV), hepatitis C virus and hepatitis E virus, or from other viralpathogens, such as paramyxoviruses: Respiratory Syncytial virus (RSV,such as F and G proteins or derivatives thereof), parainfluenza virus,measles virus, mumps virus, human papilloma viruses (HPV for exampleHPV6, 11, 16, 18), flaviviruses (e.g. Yellow Fever Virus, Dengue Virus,Tick-borne encephalitis virus, Japanese Encephalitis Virus) or Influenzavirus (whole live or inactivated virus, split influenza virus, grown ineggs or MDCK cells, or whole flu virosomes or purified or recombinantproteins thereof, such as HA, NP, NA, or M proteins, or combinationsthereof), or derived from bacterial pathogens such as Neisseria spp,including N. gonorrhea and N. meningitidis (for example capsularpolysaccharides and conjugates thereof, transferrin-binding proteins,lactoferrin binding proteins, PilC, adhesins); S. pyogenes (for exampleM proteins or fragments thereof, C5A protease, lipoteichoic acids), S.agalactiae, S. mutans H. ducreyi; Moraxella spp, including Mcatarrhalis, also known as Branhamella catarrhalis (for example high andlow molecular weight adhesins and invasins); Bordetella spp, includingB. pertussis (for example pertactin, pertussis toxin or derivativesthereof, filamenteous hemagglutinin, adenylate cyclase, fimbriae), B.parapertussis and B. bronchiseptica; Mycobacterium spp., including M.tuberculosis (for example ESAT6, Antigen 85A, -B or-C), M. bovis, M.leprae, M. avium, M. paratuberculosis M. smegmatis; Legionella spp,including L. pneumophila; Escherichia spp, including enterotoxic E. coli(for example colonization factors, heat-labile toxin or derivativesthereof, heat-stable toxin or derivatives thereof), enterohemorragic E.coli, enteropathogenic E. coli (for example shiga toxin-like toxin orderivatives thereof); Vibrio spp, including V. cholera (for examplecholera toxin or derivatives thereof); Shigella spp, including S.sonnei, S. dysenteriae, S. flexnerii; Yersinia spp, including Y.enterocolitica (for example a Yop protein), Y. pestis, Y.pseudotuberculosis; Campylobacter spp, including C. jejuni (for exampletoxins, adhesins and invasins) and C. coli; Salmonella spp, including S.typhi, S. paratyphi, S. choleraesuis, S. enteritidis; Listeria spp.,including L. monocytogenes; Helicobacter spp, including H. pylori (forexample urease, catalase, vacuolating toxin); Pseudomonas spp, includingP. aeruginosa; Staphylococcus spp., including S. aureus, S. Epidermidis;Enterococcus spp., including E. faecalis, E. faecium; Clostridium spp.,including C. tetani (for example tetanus toxin and derivative thereof),C. botulinum (for example Botulinum toxin and derivative thereof), C.difficile (for example clostridium toxins A or B and derivativesthereof) Bacillus spp., including B. anthracis (for example botulinumtoxin and derivatives thereof); Corynebacterium spp., including C.diphtheriae (for example diphtheria toxin and derivatives thereof);Borrelia spp., including B. Burgdorferi (for example OspA, OspC, DbpA,DbpB), B. garinii (for example OspA, OspC, DbpA, DbpB), B. afzelii (forexample OspA, OspC, DbpA, DbpB), B. andersonii (for example OspA, OspC,DbpA, DbpB), B. Hermsii; Ehrlichia spp., including E. equi and the agentof the Human Granulocytic Ehrlichiosis; Rickettsia spp, including R.rickettsii; Chlamydia spp., including C. Trachomatis (for example MOMP,heparin-binding proteins), C. pneumoniae (for example MOMP,heparin-binding proteins), C. psittaci; Leptospira spp., including L.interrogans; Treponema spp., including T. pallidum (for example the rareouter membrane proteins), T. denticola, T. hyodysenteriae; or derivedfrom parasites such as Plasmodium spp., including P. Falciparum;Toxoplasma spp., including T. gondii (for example SAG2, SAG3, Tg34);Entamoeba spp., including E. histolytica; Babesia spp., including B.microti; Trypanosoma spp., including T. cruzi; Giardia spp., includingG. lamblia; Leshmania spp., including L. major; Pneumocystis spp.,including P. Carinii; Trichomonas spp., including T. vaginalis;Schisostoma spp., including S. mansoni, or derived from yeast such asCandida spp., including C. albicans; Cryptococcus spp., including C.neoformans, as described in PCT Patent Publication No. WO 02/083214,entitled “Vaccine Delivery System”, the entire content of which isincorporated herein by reference.

These also include other preferred specific antigens for M.tuberculosis, for example Tb Ra12, Th H9, Tb Ra35, Tb38-1, Erd 14, DPV,MTI, MSL, mTTC2 and hTCC1. Proteins for M. tuberculosis also includefusion proteins and variants thereof where at least two, preferablythree polypeptides of M. tuberculosis are fused into a larger protein.Preferred fusions include Ral2-TbH9-Ra35, Erd14-DPV-MTI, DPV-MTI-MSL,Erd14-DPV-MTI-MSL-mTCC2, Erd14-DPV-MTI-MSL, DPV-MTI-MSL-mTCC2,TbH9-DPV-MTI. Most preferred antigens for Chlamydia include for examplethe High Molecular Weight Protein (HWMP), ORF3, and putative membraneproteins (Pmps). Preferred bacterial vaccines comprise antigens derivedfrom Streptococcus spp, including S. pneumoniae (for example capsularpolysaccharides and conjugates thereof, PsaA, PspA, streptolysin,choline-binding proteins) and the protein antigen Pneumolysin (BiochemBiophys Acta, 1989,67,1007; Rubins et al., Microbial Pathogenesis,25,337-342), and mutant detoxified derivatives thereof. Other preferredbacterial vaccines comprise antigens derived from Haemophilus spp.,including H. influenzae type B (“Hib”, for example PRP and conjugatesthereof), non typeable H. influenzae, for example OMP26, high molecularweight adhesins, P5, P6, protein D and lipoprotein D, and fimbrin andfimbrin derived peptides or multiple copy variants or fusion proteinsthereof. Derivatives of Hepatitis B Surface antigen are well known inthe art and include, inter alia, PreS1, PreS2 S antigens. In onepreferred aspect the vaccine formulation of the invention comprises theHIV-1 antigen, gp120, especially when expressed in CHO cells. In afurther embodiment, the vaccine formulation of the invention comprisesgD2t as hereinabove defined.

In addition to the delivery of substances listed above, the device andmethod can also be used for withdrawing a substance from a patient, ormonitoring a level of a substance in the patient. Examples of substancesthat can be monitored or withdrawn include blood, intersitial fluid orplasma. The withdrawn substances may then be analyzed for analytes,glucose, drugs and the like.

The embodiment of the present invention described above is a push-buttondesign wherein the device is first energized, then positioned andaffixed to a skin surface, and activated by gently pressing a slidebutton as shown in FIGS. 11A through 11C. FIG. 11A is a cross-sectionalview (6-6 in FIG. 1) of the first embodiment shown in FIG. 1 prior toenergizing and activation. FIG. 1B is a cross-sectional view of thefirst embodiment shown after energizing and prior to activation, andFIG. 11C is a cross-sectional view of the first embodiment afteractivation.

Specifically, as shown in FIGS. 11A and 11B, the user first removes thedevice of FIG. 11A from a sterile packaging and energizes the systemprior to adhering the device to the skin by removing the pull handle 260from the bottom surface of the device as shown in FIG. 11B, in a motionsimilar to opening a soda can or peeling open an orange. The pull handle260 is positioned and extends to one side of the device thereby creatinga mechanical advantage for the removal of the pull handle and attachedretaining pin 140, which can be removed with no more than a reasonableamount of force that can be exerted by a wide range of users (i.e.typically less than 3 pounds).

As shown in FIG. 11B, the removal of the pull handle 260 removes theretaining pin 140, and can also simultaneously remove an adhesive cover(not shown) and/or a needle cap 240, as described in greater detailbelow. In yet another version of this embodiment, the pull handle 260can be incorporated with the product packaging, such that when thepackage is opened and the device is removed, the retaining pin 140,adhesive cover and/or the needle cap 240 is also removed.

Upon removal of the device from the package and prior to use, thefeatures described above allows the user to then inspect both the deviceand the contents therein, including inspection for missing or damagedcomponents, expiration dates(s), hazy or color-shifted drugs, and soforth. After use, the user can once again inspect the device to ensurethe entire dose was delivered. In this regard, the device can include anadministered dose indicator for example, a readable gauge area that isat least 20% of the surface area of the device housing and accurate towithin +/−10% of the labeled dose.

Once the retaining pin 140 has been pulled a sufficient distance fromthe device to disengage from the spring, the fingers of the Bellevillespring 130 are released and are free to drop against the reservoir film170 within the device. The activation button 360 and button slide 320 ofthe button subassembly 300 can be either interlocked with, and/orshielded by the pull handle 260, such that the activation button 360cannot be pushed until the pull handle 260 has been removed, thuspreventing inadvertent activation or incorrect order of operation by theuser. Once removal of the pull handle 260, retaining pin 140, adhesivecover and needle cap 240 is accomplished as shown in FIG. 11B, thedevice is energized and ready for positioning and activation. Thisenergizing step releases the Belleville spring 130 allowing it to pressagainst the flexible film 170 of the reservoir subassembly 100,pressurizing the reservoir and the substance communication path up tothe septum 160, and prepares the device for activation.

The next step is the positioning and application of the device to theuser's skin surface. Like a patch, the user firmly presses the deviceonto the skin and the lower housing 210 includes a bottom surface thatallows for the adhesive layer 250 to secure the device to the skin ofthe user. This bottom surface of the lower housing 210 can be flat,contoured, or shaped in any suitable fashion, and includes an adhesivelayer 250 thereon, which would most likely be covered prior to shipping.Prior to use, the user peels back the adhesive covering, such as a filmcovering the adhesive, thereby exposing the adhesive for placementagainst the skin. The adhesive should preferably adhere to the bottomsurface of the device with a peel force of not less than 2 pounds, andinclude a covering that should preferably release from the adhesive witha peel force of less than ½ pound. Once removed, the user is then ableto place the device against the skin and press to ensure proper adhesion(i.e. application of a vertical load of 3 pounds). In versions of theembodiment in which a removable needle cover 240 is provided, the needlecover should preferably remove from the device with a force not toexceed 2 pounds.

Once properly positioned, the device is activated by sliding the button360 and attached button slide 320 of the push button subassembly 300towards the center of the device as shown in FIG. 11C. With no more thana reasonable amount of force applied by the user (i.e. between 2 and 4pounds), the activation button can be depressed completely to allowactivation. The button and button slide extends within the device andincludes at least one slot which, in a non-release position, holds thepatient needle manifold 220 up against the compressive force of one ormore driving springs 310.

As the button is pushed by the user, the first event to occur is thebutton pushing the septum needle 330 through the septum needle boot 340,and then through the septum 160, creating a flow path between thereservoir and the patient needles. As noted above, the “shipping”position has already brought the septum boot and septum into contact.Further motion of the button then releases the patient needle manifold220 as described above, allowing the patient needles 222 to seat intothe skin of the patient driven by the force of one or more drivingsprings 310. At this point, the button 360 and button slide 320 locksinto place giving a positive audible and tactile feedback to the userindicating that infusion has begun.

The button subassembly 300 sequence of operation described above can bevaried in other embodiments of the same or similar device. In one suchembodiment for example, as the button is pushed by the user, the firstevent to occur is the patient needle manifold 220 releasing and allowingthe patient needles 222 to seat into the skin of the patient driven bythe force of the driving springs 310. Further motion of the button thenpushes the septum needle 330 through the septum needle boot 340 andseptum 160 to create a fluid path. Either method can be implemented, butfailure modes of each can be different. For example, in an operationsequence in which flow is initiated before the patient needle manifoldis released, if the patient needles fail to seat properly a wetinjection will typically occur.

The flexible tubing 350 in each embodiment connects the septum needle330 or septum needle manifold 322 now in fluid communication with thereservoir, to the patient needle manifold 220 now in fluid communicationwith the user, and is sufficiently flexible to allow the patient needlemanifold to move independently of any other device component. Inaddition, as with the tortuous path established by the patient needlemanifold channels described above, the tubing 350 can also serve as aflow restriction where required.

Once activated, the user typically leaves the device in position, or“wears” the device, for some period of time, such as ten minutes toseventy-two hours for complete delivery of the device contents, and thenremoves and discards the device with no damage to the underlying tissue.However, upon intentional or accidental removal, one or more safetyfeatures can deploy as described in greater detail below to shield theexposed needles resulting from activation. The safety features howevercan be configured to not deploy if the button and button slide has notbeen pushed and the patient needles extended.

Safety Features

To prevent inadvertent or accidental needle sticks, intentional re-useof the device, and to shield exposed needles, a locking needle safetymechanism can be provided and activated automatically immediately uponremoval of the device from the skin surface.

In one version of a safety feature embodiment, a passive rotatingpatient needle cover as shown in FIGS. 17A and 17B is provided. FIG. 17Ais a perspective view of a safety shield feature of an embodiment of thepresent invention before energizing and activation, and FIG. 17B is aperspective view of the safety shield feature after energizing andactivation.

The rotating shield 230 can be powered by a preloaded torsion spring232, shown in FIG. 10B, and remains loaded in an “up” rotated positionuntil the button of the push button subassembly is pressed. The shield230 is then free to rotate, but is prevented from rotating to a fulldeployment position by the presence of the user's skin against theadhesive covered surface of the device. When the device is no longeragainst the user's skin, such as when the device is removed or fallsfree, the shield 230 is no longer obstructed by the skin surface androtates about 180 degrees, and is thereafter locked into place, fullycovering the patient needles 222 and preventing needle stick injuries.

In another version of a safety feature embodiment, a safety housing isprovided as shown in FIGS. 18A and 18B which provides in part, a flatsurface portion 252 that is in contact with the patient's skin. FIG. 18Ais a perspective view of a safety shield feature of an embodiment of thepresent invention before energizing and activation, and FIG. 18B is aperspective view of the safety shield feature after energizing andactivation.

The surface 252 also includes an adhesive disposed thereon such thatwhen the device is removed by the patient from the skin, the adhesivewill act to deploy (i.e., retract or extract), the safety housing 254from the interior of the device, thereby shielding the patient needles222 which otherwise would be exposed upon removal from the patient. Theextended safety housing 254 is then locked into place as shown in FIG.18B and prevents accidental injury or exposure to the patient needles.

Still other versions of a safety feature embodiment include a flexiblepatient needle cap 240 which serves to protect the patient needles andprovide a sterile barrier. The needle cap can serve to protect thepatient needles during device manufacture, protect the user prior touse, and provide a sterility barrier at any point prior to removal. Theneedle cap 240 can be attached via a press fit with the patient needlemanifold 220, and further provides a flexible member 242 which can beused to secure the cap to the pull handle 260. As described above, theremoval of the retaining pin 140 can also serve to remove the needle cap240, and the cap and/or pull handle can further provide an interlockwith the button of the push button subassembly.

Yet another active safety device feature can be provided separately, orin combination with the features described above, which allows the userto position or activate the shield when required. For example, thesafety feature may include on or more lever or rotating mechanisms asdescribed above, which may be manually toggled, or flipped, between anexposed and a shielded position, allowing the user to actively shieldthe patent needles after use and prevent accidental injury or exposureto the needles.

In each safety device version described above, the force to deploy thesafety mechanisms described is less than the peel force to remove thedevice from the skin surface, and typically require an applied force todefeat the locking mechanism of more than 3 pounds. For example, thesafety mechanisms should each provide needle tip protection from anapplied finger tip load of 2 pounds. Additional details of an extendingshield and use are further discussed in U.S. patent application Ser. No.60/397,038, and Ser. No. 60/407,284, referenced above, the entirecontents of each being incorporated herein by reference. Additionaldetails of a rotating shield and use are further discussed in U.S.patent application Ser. No. 60/447,359, Ser. No. 60/450,680, and Ser.No. 60/450,681, referenced above, the entire contents of each beingincorporated herein by reference.

In addition to the performance advantages described above, anotheradvantage of the embodiment of FIG. 1 described above is the ability tomake two or more distinct, self-contained subassemblies that allow forassembly flexibility. Each subassembly is self contained and stable, andprovides the ability to separate the reservoir assembly from remainingcomponents, allowing separate filling and inspection of the reservoir,while preventing the unnecessary handling of the remaining components.Additionally, should any of the additional components be discarded, thecostly reservoir contents can be excluded. Also, the reservoir containsno unnecessary parts and as a result, brings a low particle load intofilling operations. Also, all stored energy components are in the bodysubassembly so they cannot be inadvertently deployed during filling ofthe reservoir. Specifically, no springs are included in the reservoirwhich prevents the chance of unwanted spring release during filling. Asnoted, minimal extraneous components in the reservoir reduce particleload, and only contains necessary components, such as the reservoir,lid, septum and stopper. No dangling parts are present, and remainingparts for remaining subassemblies typically require only drop-inassembly steps.

A further advantage of the embodiment of FIG. 1 described above includesthe location of patient needles near the center of the device footprint.Such placement reduces the effects of needle displacement due to devicemovement, such as “rocking”. The patient needle manifold is constructedhaving a low mass, due in part to providing a separate manifold for theseptum, thus providing a higher patient needle manifold velocity duringactivation. The patient needle manifold is provided with independentdirect drive of patient needles, as the drive springs are locateddirectly over the patient manifold, and serve to drive the patientneedle manifold exclusively. The septum penetration force and bootcollapse force have no influence on patient needle manifold movement.Additionally, there is room to include larger needle spacing and a loweractivation force is sufficient, however, inadvertent activation due tosuch lower forces is prevented by numerous activation lockouts.

Sufficient room is also provided for a traditional urethane septumneedle boot, as well as sufficient room allowing the use of flexibletubing, or any number of flow restrictors, such as capillary tubes, forflow restriction. This can be provided while still maintaining a smallerdevice footprint. Additionally, the reservoir can be located on top ofthe device, which can allow full and unobscured view of the drugreservoir through a transparent component, allowing view of thereservoir contents to the user or manufacturer.

Second Embodiment

A second embodiment of the device, shown in FIGS. 19A and 19B, is apush-button design 400 wherein the activation and energizing of thedevice is accomplished in a single multi-function/step process. FIG. 19Ais an exploded perspective view of a second embodiment of a patch-likeinjector or infuser system using a side push button, FIG. 19B is across-sectional view of the patient needle/septum needle manifold systemof the second embodiment, FIG. 19C is a cross-sectional view of thesecond embodiment shown in FIG. 19A prior to energizing and activation,and FIG. 19D is a cross-sectional view of the second embodiment shown inFIG. 19A after energizing and activation.

The device of FIGS. 19A through 19D includes a top housing 410 and rigidbottom 415, a spring lock pin 420, a push button 430, a manifold 440, aBelleville spring 460, and a reservoir lid 480. The manifold 440 furtherincludes one or more patient needles 442 and at least one septum needle444 to pierce a septum 486.

The device of FIGS. 19A and 19C is activated and energized by pressingthe slide button 430 such that cams 431 and 432 on an inner portion ofthe button lift the spring lock pin 420 and release the spring 460thereby pressurizing the reservoir system. As the button 430 continuesalong its travel as shown in FIG. 19D, the button engages a number ofcam mechanisms which lower the needle assembly and manifold 440, havingboth the patient needles 442 and the septum needle 444 (positioned inthe same direction), as shown in FIG. 19B, toward the skin of thepatient.

Specifically, in addition to energizing the reservoir of the device byreleasing the constant force spring 460, the camming surfaces on theinterior of the button 430 engage a mating surface on the needlemanifold assembly 440 thereby driving the manifold assembly toward anopening in the underside of the device. Continued travel of the buttonforces the protruding needles 442 of the needle manifold 440 into theskin of the user and causes the fluid access spike, or septum needle444, into the interior of the reservoir thereby initiating flow of thefluid from the reservoir to the skin of the user once the needles arepositioned. As the needles 442 and 444 both face the skin surface, theskin contact and bladder piercing function of each is guaranteed. Aswill be recognized by one skilled in the art, the cam surfaces on thebutton assembly can be configured to alter the speed, or rearrange thesequence of events just described. Additional details of a push-buttondesign wherein the activation and energizing of the device isaccomplished in a single multi-function/step process are furtherdiscussed in U.S. patent application Ser. No. 60/397,038, referencedabove, the entire content of which is incorporated herein by reference.

Third Embodiment

A third embodiment of the device, shown in FIGS. 20A through 20C, is apush-button design 500 wherein the bladder itself moves towards thepatient's skin and contacts a manifold having both the patient needlesand the septum needle (positioned in opposite directions), and forcesthe patient needles into the patient's skin, and the septum needle intothe septum. FIG. 20A is an exploded perspective view of a thirdembodiment of a patch-like injector or infuser system using a side pushbutton, FIG. 20B is a cross-sectional view of the third embodiment shownprior to energizing and activation and FIG. 20C is a cross-sectionalview of the third embodiment shown after energizing and activation.

The device of FIGS. 20A through 20C includes a pull pin handle 505, atop housing 510, a leaf spring 520, a reservoir top 525, a Bellevillespring 530, a reservoir lid 535, a reservoir bottom 540, a septum 545, amanifold system 550, a push button 555, a bottom housing 560, a safetyclip 565 and a needle clip 570. In a manner similar to the firstembodiment described above, the user energizes the device of the thirdembodiment shown in FIG. 20B by removing the pull pin handle 505 fromthe device. Once this is done, the device is energized as the Bellevillespring 530 is now free to press downward on the reservoir, pressurizingthe fluid within the reservoir system, and forcing the reservoirdownward for engagement as shown in FIG. 20C and described in greaterdetail below.

In the third embodiment shown in FIG. 14, the device is activated bysliding the button 555 toward the center of the device until the buttonis no longer holding the reservoir bottom 540 in place against the tophousing 510 and against the force of the leaf spring 520. Since aportion of the reservoir system, the reservoir top 525 is preferablyrigid and spring loaded, and the reservoir lid 535 is sealinglyconnected to the reservoir bottom 540, the reservoir system now movesdownward toward the patient's skin as a single unit. A septum 545 mayalso be located on the reservoir bottom 540. A needle containingmanifold 550 is attached to the rigid bladder assembly, and it too movestowards the patient's skin until the patient needles penetrate the skin.At this time, the needle manifold bottoms out on the bottom housing 560of the device. The reservoir assembly continues downward slightly andcauses the fluid access spike, or septum needle, to penetrate the septum545, thereby initiating flow of fluid from the reservoir and through thepatient needle or needles.

One unique characteristic of the third embodiment is that the septumneedle accesses the reservoir from below as the reservoir movesdownwards. This allows the device to collapse in height, and allows thedevice to have a lower profile once activated. In addition, since theseptum needle penetration is in the opposite direction of the patientneedle penetration, it does not require additional height within thedevice allowing the septum needle to be maintained in a sterilecondition without the necessity for additional interior space or overalldevice height. Additional details of a push-button design wherein thebladder itself moves towards the patient's skin and contacts a manifoldhaving both the patient needles and the septum needle are furtherdiscussed in U.S. patent application Ser. No. 60/397,038, referencedabove, the entire content of which is incorporated herein by reference.

Fourth Embodiment

A fourth embodiment of the device, shown in FIGS. 21A through 21C, is apush-button design wherein the push-button is located on the top, outersurface of the device, and the user energizes and activates the fluidflow by depressing the button to its lower-most position. FIG. 21A is anexploded perspective view of a fourth embodiment of a patch-likeinjector or infuser system using a top push button, FIG. 21B is apartial cross-sectional view of the fourth embodiment shown in FIG. 21Aprior to energizing and activation, and FIG. 21C is partialcross-sectional view of the fourth embodiment shown in FIG. 21A afterenergizing and activation.

The device of FIG. 21A includes a top push button 602, an upper housing605, leaf springs 610, a manifold assembly 615, pull pin 620, releaseguide 630, retainer 635, Belleville spring 640 and reservoir 645. Aswith the earlier embodiments described above, the adhesive 655 and 660on the bottom surface of the device is exposed and the user presses thedevice against the skin in the desired area of the body to securelyattach it. Once the device is in place and attached the user depressesthe button 602 located on the top in this embodiment. The depression ofthe button 602 forces the manifold assembly 615 located directly beneaththe button downward, and the manifold assembly contains an angledsurface that mates with a protrusion on the release guide 630. As themanifold assembly 615 travels downward, the release guide 630 movesalong the leaf springs 610 in the grooves or guides of the retainer 635toward the pull pin 620 and its attachment to the constant force spring640. The pull pin 620 is configured and shaped to fit within theretainer 635 and to be retained therein, preferably by a retaining pin625. This configuration allows the pull pin 620 to rotate freely aboutthe retaining pin 625. The release guide 630 meanwhile is forced alongthe guides within the retainer 635. The underside of the release guide630 has a chamfered surface that slides along a mating chamfered surfaceon the pull pin 620, depressing the leaf springs 610 and one end of thepull pin and causing the pull pin to rotate about the retaining pin 625and lift the other end of the pull pin where it is attached to theconstant force spring 640. This rotation and lifting overcomes theretaining force of the pull pin and causes it to release the constantforce spring and thereby energize the reservoir 645.

Occurring simultaneously with the downward travel of the push button,the manifold assembly 615 which contains a septum piercing needle orspike and the skin penetrating needle or needles is also presseddownward until the needles are fully embedded at the desired depth inthe skin. The septum piercing spike then accesses the fluid within thereservoir, before or after the reservoir is energized depending upon theconfiguration, permitting the fluid within the reservoir to flow. Aswith the embodiments described above, each configuration can be alteredto affect the timing and sequence of the events described above.Additional details of a push-button design wherein the push-button islocated on the top, outer surface of the device, and the user energizesand activates the fluid flow by depressing the button to its lower-mostposition are further discussed in U.S. patent application Ser. No.60/407,284, referenced above, the entire content of which isincorporated herein by reference.

Test Results

Various results and comparisons between embodiments of the preferreddevice and other techniques and devices are shown in FIGS. 22 through26. The graph of FIG. 22 shows the flow rate uniformity over an extendeddelivery time in vitro to establish the measured flow rate that issubsequently used in a diabetic swine trial. This is further illustratedin FIG. 26, which shows pressure versus volume delivered data inaccordance with an embodiment of the present invention. The use of theBelleville spring to apply pressure to the flexible reservoir results ina near constant delivery rate over an infusion period of 25 hours usingthe embodiment of FIG. 1 described above.

The graph of FIG. 24 shows the average blood insulin levels(pharmacokinetic response) measured in several animals over the insulindelivery period. This is initially very low, due to the diabetic stateof the animal, and then increases to much higher levels during infusion.At the end of the infusion, the insulin levels return to the lowbaseline levels. Minor peaks occur in the average baseline insulinlevels of negative control animals receiving no insulin. These peaksreflect a minimal endogenous insulin secretion by the animals inresponse to feeding times at −1, 7, 14, 21, and 28 h. The infusion dataillustrated in FIG. 22 further shows that results in accordance with anembodiment of the present invention described above are substantially asdesirable as results obtained using a standard insulin pump. Furtherdetails of pharmacokinetic profiles are discussed in a U.S. PatentApplication Publication No. 2002/0095134, entitled “Method For AlteringDrug Pharmacokinetics Based On Medical Delivery Platform”, filed Jun.29, 2001, the entire content of which is incorporated herein byreference.

The graph of FIG. 23 shows the average blood glucose level measured inseveral animals over the insulin delivery period (pharmacodynamicresponse) in accordance with an embodiment of the present invention. Theblood glucose level is influenced by feeding and any additional glucosegiven to the animal to prevent hypoglycemic injury. As a result, thereare periodic spikes in glucose level, corresponding to feeding times athours−1, 7, 14, 21, and 28. The blood glucose values of both infusor andinsulin pump treated animals fall drastically within the first 5 hoursof insulin delivery. Blood glucose levels remain substantially below theresponse of negative control diabetic animals receiving no insulin forthe remainder of the experimental period. The blood glucose effectsobtained with the infusor, as illustrated in FIG. 23, are substantiallyequivalent to the results obtained using a standard insulin pump. Notethat in both FIGS. 22 and 23, the performance of the pump and themicroinfusor are quite similar, resulting in very similar physiologicalresponses.

The graph of FIG. 25 shows the blood insulin levels (pharmacokineticresponse) measured in an animal receiving insulin from an infusordesigned to deliver a larger dose of insulin as a “metered bolus” over afew minutes time period. In the embodiment of FIG. 1, the infuserperforms substantially as well as results obtained from a subcutaneousinjection using a standard syringe.

Although only a few exemplary embodiments of the present invention havebeen described in detail above, those skilled in the art will readilyappreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe following claims.

1. A patch-like infusion device, comprising: a fluid reservoir having atleast one flexible wall; at least one patient needle in selective fluidcommunication with said reservoir; a Belleville spring having a centralaperture for applying pressure to said flexible wall to cause fluid toflow from said reservoir to said patient needle; and a pin engageablewith said central aperture and disengageable therefrom for causing saidBelleville spring to begin applying said pressure when said infusiondevice is placed into operation wherein disengagement of said pin fromsaid central aperture occurs automatically when the user performsanother operation on said infusion device wherein said operationcomprises removing a pull handle operatively coupled to said pin.
 2. Apatch-like infusion device as claimed in claim 1, wherein disengagementof said pin from said aperture provides at least one of an audibleindication and a tactile indication to a user of said infusion device.3. A patch-like infusion device as claimed in claim 1, wherein saidoperation comprises operating a pushbutton operatively coupled to saidpin.
 4. A patch-like infusion device as claimed in claim 3, wherein saidoperation comprises removing a pushbutton guard or interlock.
 5. Apatch-like infusion device as claimed in claim 1, wherein said operationcomprises operating a pull handle operatively coupled to said pin.
 6. Apatch-like infusion device as claimed in claim 3, wherein said operationof said pushbutton begins selective fluid communication of said at leastone patient needle with said reservoir.
 7. A patch-like infusion deviceas claimed in claim 6, wherein said selective fluid communication ofsaid at least one patient needle with said reservoir is by piercing aseptum engaged to said reservoir which selectively seals said reservoir.